T-cell activation plays a central role in driving both protective and pathogenic immune responses, and it requires the completion of a carefully orchestrated series of specific steps that can be preempted or disrupted by any number of critical events. Naïve T cells must receive two independent signals from antigen-presenting cells (APC) in order to become productively activated. The first, Signal 1, is antigen-specific and occurs when T cell antigen receptors encounter the appropriate antigen-MHC complex on the APC. This signal is necessary but not sufficient for the determination of the faith of the immune response. This is determined by a second, antigen-independent signal (Signal 2) which is delivered through a T cell costimulatory molecule that engages its APC-expressed ligand. This second signal could be either stimulatory (positive costimulation) or inhibitory (negative costimulation or coinhibition). In the absence of a costimulatory signal, or in the presence of a coinhibitory signal, T-cell activation is impaired or aborted, which may lead to a state of antigen-specific unresponsiveness (known as T-cell anergy), or may result in T-cell apoptotic death.
Costimulatory molecule pairs usually consist of ligands expressed on APCs and their cognate receptors expressed on T cells. The prototype ligand/receptor pairs of costimulatory molecules are B7/CD28 and CD40/CD40L.
Tumor cells often express negative costimulatory molecules and thus take advantage of the immunomodulatory activity of these molecules to evade immune surveillance. Such tumor expressed B7s serve as tumor-associated antigens (TAAs) and have become attractive cancer biomarkers as well as drug targets for active (vaccination) and passive (antibody-mediated) cancer immunotherapy providing strategies to break immune tolerance and stimulate the immune system.
Cancer vaccination involves the administration of tumor antigens and is used to break immune tolerance and induce an active T-cell response to the tumor. Vaccine therapy includes the use of naked DNA, peptides, recombinant protein, and whole cell therapy, where the patient's own tumor cells are used as the source of the vaccine.
The applications of anti-TAA antibodies for treatment of cancer include therapy with naked antibody, therapy with a drug/toxin-conjugated antibody, adoptive immunotherapy and fusion therapy with cellular immunity (development of cytotoxic T-lymphocyte (CTL) or natural killer (NK)-cell populations with anti-TAA antibody activity). The antigenic epitopes that are targeted by these therapeutic approaches are present at the cell surface, overexpressed in tumor cells compared to non-tumor cells, and are targeted by antibodies that block functional activity, inhibit cell proliferation, or induce cell death.
Negative regulators of the immune system, called immune checkpoints, play critical roles in maintenance of tolerance to self-antigens. Immune checkpoints are used by the tumor and become barriers to generating effective tumor immunity, playing important roles in restraining otherwise effective anti-tumor immunologic responses. Several immune checkpoints are negative costimulatory proteins, members of the B7/CD28 family of immune regulators. Immunomodulatory antibody therapies that target these negative regulator checkpoints, such as those directed against CTLA4 and PD-1, have demonstrated promising clinical results.
Passive immunotherapy strategies are well established in oncology and involve passive transfer of anti-cancer monoclonal antibodies as targeted therapy. In contrast, active immunotherapy strategies are aimed to elicit the body's anti-tumor immunity, and have only recently began to show success in treatment of cancer. Activating the immune system for therapeutic benefit in cancer has long been a goal in oncology. Among several active immunotherapy approaches, immunomodulatory antibody therapy refers to the use of monoclonal antibodies that directly enhance the function of components of the anti-tumor immune response, such as T cells, or block immunologic checkpoints that would otherwise restrain effective anti-tumor immunity. Recently this strategy, also named immune regulatory antibodies, has finally gained proof of concept in clinical trials. The blockade of immune checkpoints seems to unleash the potential of the anti-tumor immune response in a fashion that is transforming human cancer therapeutics. Most notably is the ability of the anti-CTLA4 antibody, Ipilimumab, to achieve a significant increase in survival for patients with metastatic melanoma, for which conventional therapies have failed. Substantial clinical responses have also been obtained in patients treated with an anti-PD-1 antibody, MDX1106.
Highly immunogenic tumors, such as malignant melanoma, are most responsive to immune system manipulation, and thus many of these treatment modalities have been first applied to patients with melanoma. However, numerous ongoing clinical studies are geared at targeting a variety of tumors by combining agents that target immune checkpoints with other more conventional approaches such as targeted therapy, chemotherapy and radiotherapy, or with other novel immunotherapeutic approaches, including therapeutic cancer vaccines. Extensive preclinical data has indeed shown that therapeutic agents that result in tumor cell death liberate tumor antigens and provide the right fuel for checkpoint-blocking antibodies even in poorly immunogenic tumors, leading to impressive therapeutic synergy among such agents. Similar observations were obtained in multiple preclinical studies, demonstrating the synergistic efficacy of therapeutic cancer vaccines and checkpoint blockade.
Such agents could be administered in conjunction with tumor-specific antigens, as an adjuvant that serves to enhance the immune response to the antigen in the patient. In addition, such agents could be of use in other types of cancer immunotherapy, such as adoptive immunotherapy, in which tumor-specific T cell populations are expanded and directed to attack and kill tumor cells. Agents capable of augmenting such anti-tumor response have great therapeutic potential and may be of value in the attempt to overcome the obstacles to tumor immunotherapy.
Regulating costimulation using agonists and antagonists to various costimulatory proteins has been extensively studied as a strategy for treating autoimmune diseases, graft rejection, allergy and cancer. This field has been clinically pioneered by CTLA4-Ig (Abatacept, Orencia®) that is approved for treatment of RA, and by the anti-CTLA4 antibody (Ipilimumab, Yervoy®), recently approved for the treatment of melanoma. Other costimulation regulators are currently in advanced stages of clinical development including anti PD-1 antibody (MDX-1106) which is in development for treatment of advanced/metastatic clear-cell renal cell carcinoma (RCC) and anti-CD40L Antibody (BG9588, Antova®) for treatment of renal allograft transplantation. Furthermore, the accumulating evidence linking regulation of costimulation and various types of infections support a promising potential for such agents as therapy for infectious diseases. In accordance with this, such agents are in clinical development for viral infections, for example the anti PD-1 Ab, MDX-1106, is being tested for treatment of hepatitis C. Another example is CP-675,206 (tremelimumab) and anti-CTLA4 Ab is in a clinical trial in hepatitis C virus-infected patients with hepatocellular carcinoma.
Accumulations of inducible regulatory T cells (iTregs) are commonly seen in many tumors, and form the major subset of immune suppressor cells in the tumor tissue. Tregs create an immunosuppressive environment and regulate anti-tumor immunity, and thus represent a major tumor resistance mechanism from immune surveillance. iTregs are therefore viewed as important cellular targets for cancer therapy.
In addition to their function in dampening effector T cell responses, multiple immune-checkpoint receptors, such as CTLA4 and PD-1, and others like TIM3 and LAG3, are expressed at high levels on the surface of iTregs and directly promote Treg cell-mediated suppression of effector immune responses. Many of the immune-checkpoint antibodies in clinical testing most likely block the immunosuppressive activity of iTregs as a mechanism of enhancing anti-tumor immunity. Indeed, two important factors in the mode of action of CTLA4 blockade by ipilimumab are the enhancement of effector T cell activity, and inhibition of Treg immunosuppressive activity.
Several strategies, used alone or in combination with conventional treatments or immunotherapies, are in development in order to disarm iTregs and restore antitumor functions of effector T cells.
B cells play a critical role in recognition of foreign antigens and they produce the antibodies necessary to provide protection against various type of infectious agents. T cell help to B cells is a pivotal process of adaptive immune responses. Follicular helper T (Tfh) cells are a subset of CD4+ T cells specialized in B cell help (reviewed by Crotty, Annu. Rev. Immunol. 29: 621-663, 2011). Tfh cells express the B cell homing chemokine receptor, CXCR5, which drives Tfh cell migration into B cell follicles within lymph nodes in a CXCL13-dependent manner. The requirement of Tfh cells for B cell help and T cell-dependent antibody responses, indicates that this cell type is of great importance for protective immunity against various types of infectious agents, as well as for rational vaccine design.